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Keywords:

  • alkanes;
  • C[BOND]H activation;
  • C[BOND]H functionalization

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

Transition-metal-catalyzed C[BOND]H activation has recently emerged as a powerful tool for the functionalization of organic molecules. While many efforts have focused on the functionalization of arenes and heteroarenes by this strategy in the past two decades, much less research has been devoted to the activation of non-acidic C[BOND]H bonds of alkyl groups. This Minireview highlights recent work in this area, with a particular emphasis on synthetically useful methods.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

The traditional approach used by organic chemists to functionalize a molecule consists of transforming a pre-existing functional group (FG) to obtain the desired chemical function (Scheme 1, left).

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Scheme 1. Functional group transformation vs. C[BOND]H functionalization.

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Because unactivated sp2 and sp3 carbon–hydrogen bonds (abbreviated to C[BOND]H bonds hereafter) are ubiquitous in organic compounds, it is easy to conceive that the direct functionalization of these bonds constitutes a faster and more atom-economical synthetic approach (Scheme 1, right). Thus, the use of C[BOND]H bonds as functional groups similar to carbon–halogen bonds represents a powerful, valuable, straightforward strategy for the construction of complex organic frameworks.1 This concept is gradually modifying organic chemistry because it provides chemists in both the academic and industrial worlds with new disconnection strategies that give access to molecules with original structures and properties in a more simple, efficient, and ecological manner.

Despite intrinsic reactivity and selectivity issues, C[BOND]H functionalization methods have grown exponentially in recent decades thanks to the development of homogeneous catalysis.2 Transition-metal-catalyzed C[BOND]H functionalization reactions can be separated into two different classes that involve two markedly different types of mechanisms (Scheme 2):2g, 3 1) Outer-sphere-type mechanisms, including C[BOND]H insertions and C[BOND]H oxidations, in which the C[BOND]H bond cleavage does not produce a carbon–metal bond and which are particularly suited to the functionalization of C(sp3)[BOND]H bonds (Scheme 2a);4 and 2) inner-sphere-type mechanisms in which the C[BOND]H bond cleavage produces an organometallic species, which can be applied to a wide variety of C[BOND]H bonds (Scheme 2b).5 The term “C[BOND]H activation” has been used throughout the literature with different meanings, but often as a synonym of “transition-metal-catalyzed C[BOND]H functionalization”, which is a very general definition.24 Herein, we propose to adopt the more precise “organometallic” definition for C[BOND]H activation as being “the formation of a carbon–metal bond by cleavage of a carbon–hydrogen bond”, according to Labinger and Bercaw.6 In other words, catalytic C[BOND]H activation will hereafter refer to C[BOND]H functionalization reactions involving inner-sphere-type mechanisms (Scheme 2b).

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Scheme 2. Classification of transition-metal-catalyzed C[BOND]H functionalization; [M]=transition-metal complex.

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Catalytic C[BOND]H activation methods have been widely developed for the functionalization of arenes and heteroarenes in the past two decades, and they have been the subject of several accounts and reviews.7 In comparison, much less research has been devoted to the catalytic activation of non-acidic C[BOND]H bonds of alkyl groups. In principle, it should be possible to activate inert C(sp3)[BOND]H bonds similarly to C(sp2)[BOND]H bonds; however, the former have no empty low-energy orbitals or filled high-energy orbitals that could readily interact with orbitals of the metal center, as is the case with unsaturated hydrocarbons. Therefore, catalytic C(sp3)[BOND]H activation seems to represent a significantly bigger challenge.

This review article will broadly survey the literature dealing with the catalytic C[BOND]H activation of otherwise unreactive C(sp3)[BOND]H bonds in organic synthesis up to early 2009, with a particular emphasis on synthetically useful methods that were used or could be potentially used for the construction of complex organic molecules. The catalytic C[BOND]H activation of simple, unfunctionalized alkanes, which has been reviewed previously, will be discussed only briefly.2, 3 Catalytic C(sp3)[BOND]H functionalizations involving outer-sphere-type mechanisms will also be excluded because they now constitute well-established synthetic methods and they have also been extensively reviewed.24

Heteroatom-Directed C[BOND]H Activation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

A majority of intramolecular C(sp3)[BOND]H activation methods proceed by a heteroatom-directed coordination/activation mechanism (Scheme 3).8 Coordination of the catalyst to the substrate is allowed by the introduction of a chelating/donating group, which can facilitate C[BOND]H activation and subsequent functionalization. This strategy is generally regioselective and avoids the introduction/loss of a functional group such as a halogen atom.

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Scheme 3. Heteroatom-directed C[BOND]H activation; DG=directing group.

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C[BOND]C and C[BOND]Si coupling: Early work demonstrated that regioselective C(sp3)[BOND]H activation could be achieved intramolecularly by heteroatom-assisted coordination in stoichiometric organometallic reactions.8 This concept was used by Sames, as well as others, in the synthesis of natural products and bioactive molecules.9, 10 For instance, in the synthesis of the teleocidin B-4 core (Scheme 4), Sames et al. reported the selective activation of the C(sp3)[BOND]H bond of a tert-butyl group under assistance, by coordination to an imine and a methoxy group. The C[BOND]H activation step generated a stable palladacycle11 that subsequently reacted with a boronic acid to generate the C[BOND]C coupling product after in situ decoordination.

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Scheme 4. Synthesis of the teleocidin B-4 core by stoichiometric C[BOND]H activation/C[BOND]C coupling; DMF=dimethylformamide.

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Yu et al. developed a catalytic protocol for the pyridine-directed, PdII-catalyzed alkylation of C(sp2)[BOND]H and C(sp3)[BOND]H bonds with either methylboroxine or alkylboronic acids (Scheme 5).12 A mixture of oxidants (silver oxide and benzoquinone (BQ)) was used to regenerate the active PdII species. The reaction was complete within 6 h at 100 °C, and afforded moderate yields of C[BOND]C coupling product. The reaction was compatible with ether, alcohol, and ester groups, but was limited to alkylboronic acids. Mechanistic investigations alluded to an unusual pyridine–boroxine complex assisting the C[BOND]H activation step.

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Scheme 5. Palladium(II)-catalyzed C[BOND]H activation/C[BOND]C coupling with a pyridine directing group and boronic acids.

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In a later report, these authors described a catalytic coupling of both ortho C[BOND]H bonds in benzoic acids and β-C[BOND]H bonds in aliphatic acids with organoboron reagents through a similar mechanism (Scheme 6).13 The reaction proceeded via the in situ formation of the corresponding carboxylate directing group, which engaged in a C[BOND]H activation/cross-coupling step to give the β-arylated product in moderate yield. This work was extended to more strongly binding O-methyl hydroxamic acids as directing groups, which resulted in improved yields by using BQ and either Ag2O or air as stoichiometric oxidant (Scheme 7).14 In the latter case, a longer reaction time is required.

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Scheme 6. Palladium(II)-catalyzed C[BOND]H activation/C[BOND]C coupling with a carboxylic acid directing group and a boronate.

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Scheme 7. Palladium(II)-catalyzed C[BOND]H activation/C[BOND]C coupling with an O-methyl hydroxamic acid directing group and boronic acids.

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A further extension to enantioselective C(sp3)[BOND]H activation/C[BOND]C coupling by using a pyridine directing group was recently disclosed by Yu and co-workers (Scheme 8).15 The chiral catalyst was composed of palladium(II) and a chiral cyclopropanecarboxylate ligand and gave a modest yield and enantioselectivity of the C[BOND]C coupling product with n-butylboronic acid. Better yields and enantiomeric excesses (ees) of up to 95 % were obtained for the analogous C(sp2)[BOND]H activation/C[BOND]C coupling, but this constitutes the first example of a catalytic asymmetric C(sp3)[BOND]H activation, which should stimulate further research in this area.

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Scheme 8. Enantioselective palladium(II)-catalyzed C[BOND]H activation/C[BOND]C coupling; Boc=tert-butyloxycarbonyl.

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In the same trend involving coupling of an organometallic intermediate with a boronate, Sames et al. described the ruthenium-catalyzed C(sp3)[BOND]H activation/C[BOND]C coupling of pyrrolidine-derived amidines (Scheme 9).16 The reaction proceeded at 150 °C in 4 to 19 h and gave good yields and trans diastereoselectivity. It was proposed to involve nitrogen-directed C[BOND]H activation to generate a ruthenium hydride intermediate that is trapped by ketone insertion (see Scheme 9), followed by transmetalation with the arylboronate and reductive elimination to give the coupling product. Of the several directing groups that were reported, dihydropyrrole, pyridine and pyrimidine proved to be the most efficient ones.

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Scheme 9. Ruthenium-catalyzed C[BOND]H activation/C[BOND]C coupling with a dihydropyrrole directing group and a boronate.

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Earlier work by Murai and co-workers had already described similar pyridine-directed intramolecular C(sp3)[BOND]H activation in the direct propionylation of pyrrolidines and piperazines under rhodium catalysis (Scheme 10).17 This reaction was relatively slow (40–60 h) and required rather forcing conditions (160 °C, 10 atm CO, 5 atm ethylene), affording the corresponding ketone in low-to-good yields depending on the nature of the pyridine substituents. The reaction presumably involves a pyridine-directed C[BOND]H activation α to the pyrrolidine nitrogen, subsequent ethylene insertion into the hydride–rhodium bond (see Scheme 10), then CO insertion and reductive elimination. The mechanism entailed in the C(sp3)[BOND]H bond cleavage has not been elucidated but could imply either oxidative addition, hydride elimination from a 1,3-diaza-π-allyl-rhodium complex, or participation of an iminium intermediate.

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Scheme 10. Rhodium-catalyzed C[BOND]H activation/ethylene insertion/CO insertion.

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Later, Kakiuchi et al. reported the chelation-assisted regioselective silylation of aromatic C(sp2)[BOND]H and benzylic C(sp3)[BOND]H bonds in low-to-moderate yields by using [Ru3(CO)12] as the catalyst, a hydrosilane as the reagent, and norbornene as the hydrogen acceptor (Scheme 11).18 This methodology showed a broad scope in terms of N-directing groups (pyridines, pyrazoles, and hydrazones), with some limitations in the nature of the hydrosilane reagent (HSiEt3, HSiPh3 and HSiMe2(tBu) were successfully used). The reaction was also affected by the nature of the substituent on the pyridine directing group, with steric bulk around the nitrogen blocking the reactivity.

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Scheme 11. Ruthenium-catalyzed C[BOND]H activation/C[BOND]Si coupling.

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Shibata et al. described the use of a cationic iridium(I)–BINAP (BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) catalyst in the alkenylation of arylamides α to the nitrogen with alkynes (Scheme 12).19 This transformation, in which the amide oxygen serves as the directing atom, displays a rare case of selective alkyl C(sp3)[BOND]H activation over aromatic C(sp2)[BOND]H activation. It proceeded at a rather high temperature (135 °C) with reaction times ranging from 6 to 72 h, and gave good yields of alkyne insertion product. Mechanistic studies by using deuterium labeling suggested C(sp3)[BOND]H activation as the initial step of the reaction, followed by alkyne insertion.

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Scheme 12. Iridium-catalyzed C[BOND]H activation/alkyne insertion; cod=1,5-cyclooctadiene.

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Reactions involving a PdII/PdIV mechanism are poorly understood and there is still a great deal of discussion among the scientific community with respect to the matter.20 However, in the field of C(sp3)[BOND]H activation, several systems have been described and rationalized by this mechanism. In that prospect, and during the course of a study on C(sp2)[BOND]H arylation, Daugulis et al. reported the arylation of a C(sp3)[BOND]H bond of 2-ethylpyridine by 4-iodotoluene in the presence of silver acetate and catalytic palladium acetate (Scheme 13).21 The reaction is extremely slow (≈2 d) even at 130 °C, and gave a moderate amount of product.

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Scheme 13. Palladium(II)-catalyzed C[BOND]H activation/C[BOND]C coupling with a pyridine directing group and an iodoarene.

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A subsequent report by the same group described a related arylation process with iodoarenes (Scheme 14).22 This method allowed for the overall β-arylation of carboxylic acid derivatives and γ-arylation of amine derivatives in good yields with a low catalyst loading (up to 650 turnovers) in solvent-free conditions. It is worth noting that the reaction is selective for iodoarenes because bromoarenes remained intact. For these two transformations, the authors proposed a mechanism that involved the formation of a tricoordinate palladacycle by C[BOND]H activation (see Scheme 14), followed by oxidative addition of the iodoarene to form a palladium(IV) intermediate that, by reductive elimination, would give the C[BOND]C coupling product. Shortly thereafter, Corey and co-workers reported the β- and γ-arylation of amides derived from α-amino acids with aryl iodides, which presumably occurred by a similar mechanism.23

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Scheme 14. Palladium(II)-catalyzed C[BOND]H activation/C[BOND]C coupling with a chelating directing group and an iodoarene. X=CH2, CO: aromatic tether; Y=CO: carboxylic acid β-arylation; Y=CH2: amine γ-arylation.

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A related work by Yu and co-workers described the β-arylation of simple aliphatic acids (Scheme 15).13 According to the authors, the observed formation of diarylated products could lend support to a PdII/PdIV mechanism in which PdII remains bound to the carboxylate, resulting in additional arylation.

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Scheme 15. Palladium(II)-catalyzed C[BOND]H activation/C[BOND]C coupling with a carboxylic acid directing group and an iodoarene.

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The same group recently reported the β-arylation of N-pentafluorophenyl amides (Scheme 16).24 Depending on the reaction substrate, mono- or diarylation products were obtained. Amides derived from drugs such as ibuprofen could be functionalized using this method. In this case, the reaction presumably proceeds through a Pd0/PdII mechanism, starting with oxidative addition of the aryl iodide to palladium and followed by coordination of the resulting PdII complex to the oxygen of the deprotonated amide. Remarkably, no N-arylation product was observed with this system.

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Scheme 16. Palladium(0)-catalyzed C[BOND]H activation/C[BOND]C coupling with a N-pentafluorophenyl amide directing group and an iodoarene.

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Fagnou et al. reported an elegant and efficient site-selective C(sp2)[BOND]H/C(sp3)[BOND]H arylation of azine and diazine N-oxides that also involved a Pd0/PdII catalytic cycle (Scheme 17).25 This methodology applies to a broad range of N-oxides and aryl halides. Interestingly, the selectivity of C(sp2)[BOND]H vs. C(sp3)[BOND]H arylation is largely influenced by the nature of the base, with a strong base such as NaOtBu being compulsory for C(sp3)[BOND]H arylation, which is probably directed by the N-oxide oxygen (see Scheme 17).

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Scheme 17. Palladium(0)-catalyzed site-selective C(sp2)[BOND]H/C(sp3)[BOND]H arylation of azine N-oxides; dba=dibenzylideneacetone.

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A different strategy was adopted by Sanford et al. for directed C(sp2)[BOND]H and C(sp3)[BOND]H arylation. They used the iodine(III) reagent [Ph2I][BF4] and palladium(II) catalysis to convert a methylquinoline to the corresponding C(sp3) arylation product (Scheme 18).26 Recent mechanistic studies indicate that the reaction proceeds via a bimetallic high oxidation state palladium species.27

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Scheme 18. Palladium(II)-catalyzed C[BOND]H activation/C[BOND]C coupling with a quinoline directing group and a diaryliodonium salt.

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In a conceptually different approach, concurrent work by the groups of Doye (Ti)28 and Schafer (Ti, Zr)29 described interesting intra- and intermolecular hydroaminoalkylations of alkenes by C(sp3)[BOND]H bond activation α to the nitrogen of primary and secondary amines (Scheme 19). Seminal work by Hartwig et al. (Ta, Nb)30 and by Holmes et al. (Ta, Zr)31 suggested that these reactions proceed via the formation of an azametallacyclopropane followed by alkene insertion and protolysis. Moderate-to-high yields were achieved with a range of terminal alkenes, and good regioselectivity was observed in favor of the linear product (L) in the intermolecular version.28 However, these reactions required a high temperature (≥145 °C) and a long reaction time irrespective of the nature of the catalyst.

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Scheme 19. Early transition-metal-catalyzed C[BOND]H activation/alkene insertion directed by an amino group.

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C[BOND]O, C[BOND]N, and C[BOND]halogen bond formation: Sanford and co-workers demonstrated that directed C(sp3)[BOND]H activation could be coupled to oxidation under palladium catalysis to give esters and ethers (Scheme 20).32, 33 The oxidation was achieved through the use of [PhI(OAc)2] as a stoichiometric oxidant. The reaction proceeded at 100 °C, affording moderate-to-good yields of mono- or polyoxidation product, and proved highly regioselective because mainly β-methyl groups were activated. Mechanistic studies by Sanford et al.,34 based on seminal work by Canty et al.,35 led to the isolation of a PdIV complex from the stoichiometric oxidation of a palladacycle with PhI(O2CPh)2, and supported a PdII/PdIV mechanism.

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Scheme 20. Palladium(II)-catalyzed C[BOND]H activation/acetoxylation with pyridine and oxime ether directing groups.

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This C[BOND]H oxidation method was nicely extended to C[BOND]H amination shortly thereafter (Scheme 21).36 Sulfonamides and amides were obtained under palladium(II) catalysis by using the same type of O-methyl oxime or heterocyclic nitrogen directing group. The reaction was proposed to proceed via intramolecular C[BOND]H activation followed by insertion of a nitrene generated in situ from the corresponding primary amide or sulfonamide and potassium persulfate.

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Scheme 21. Palladium(II)-catalyzed C[BOND]H activation/amidation; DCE=1,2-dichloroethane.

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The halogenation of C(sp3)[BOND]H bonds according to a related mechanism was also reported by Sanford and co-workers (Scheme 22).37 Especially worth noting is the C[BOND]H fluorination reaction, which was performed chemoselectively on a methylquinoline substrate in the presence of an N-fluoropyridinium salt.

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Scheme 22. Palladium(II)-catalyzed C[BOND]H activation/fluorination.

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A related work on the selective acetoxylation and iodination of methyl groups located at the α position of an oxazoline directing group was reported by Yu et al. (Scheme 23).38 These two types of reactions proceeded under particularly mild conditions in moderate-to-good yields. The use of chiral bulky oxazolines allowed the diastereoselective iodination/acetoxylation of prochiral methyl groups to be performed, and gave a good diastereomeric ratio. Mechanistic studies led to the isolation of a trinuclear bis-μ-acetatopalladium(II) intermediate that arises from electrophilic C(sp3)[BOND]H bond cleavage. During the reaction, this complex presumably undergoes further oxidation to give rise to a PdIV species, which would give the acetoxylated or iodinated product by reductive elimination. The iodination of two methyl groups was also performed on these oxazoline systems and applied to an original synthesis of cyclopropanes.39 The same group successfully extended this oxidation methodology to Boc-protected N-methylamines by using in situ-generated IOAc (Scheme 24).40

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Scheme 23. Palladium(II)-catalyzed C[BOND]H activation/acetoxylation and iodination with an oxazoline directing group; TBS=tert-butyldimethylsilyl.

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Scheme 24. Palladium(II)-catalyzed C[BOND]H activation/acetoxylation with a Boc directing group.

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Finally, a report by Chang et al. demonstrated that either PtII or PdII catalysts could activate the C(sp3)[BOND]H bond of o-alkyl-substituted aromatic carboxylic acids to generate the corresponding lactones, but with a rather limited substrate scope and in moderate yield (Scheme 25).41 The C(sp3)[BOND]H activation step is probably assisted by initial chelation of the metal center to the carboxylate. Subsequent reductive elimination with concomitant reoxidation of the metal center by adding a stoichiometric amount of copper salt completes the catalytic cycle.

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Scheme 25. Platinum(II)-catalyzed C[BOND]H activation/lactonization.

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Dehydrogenation: The dehydrogenation of alkyl groups by heteroatom-directed C[BOND]H activation to give rise to alkenes (Scheme 26) was reported by Yu et al.42 A catalytic version was devised by using benzoquinone (BQ) as the stoichiometric oxidant. The C[BOND]H activation was directed by both the amide and oxazoline nitrogens, as demonstrated by the isolation and X-ray diffraction analysis of various palladium–product complexes (see Scheme 26 for an example).

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Scheme 26. Palladium(II)-catalyzed C[BOND]H activation/dehydrogenation.

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Unsaturation-Directed C[BOND]H Activation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

Besides heteroatoms, a carbon–carbon double or triple bond can serve as a directing group for metal-catalyzed intramolecular C[BOND]H activation. In addition, because it is also a reactive group it is usually transformed in the overall process (Scheme 27). Most published research within this class of directed C(sp3)[BOND]H activation deals with allylic C[BOND]H activation.

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Scheme 27. Unsaturation-directed C[BOND]H activation.

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Allylic C[BOND]H activation: Palladium(II)-catalyzed allylic oxidation has been known since the early 1980s (Scheme 28).43 The regioselectivity of this reaction has remained an issue for a long time; acyclic internal alkenes give rise to regioisomeric mixtures of allylic acetates and terminal alkenes give rise to Wacker-type oxidation products (i.e., methyl ketones and vinyl acetates).

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Scheme 28. Palladium(II)-catalyzed allylic C[BOND]H oxidation.

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Recently, White and co-workers reported various conditions for the selective allylic oxidation of terminal olefins under palladium(II) catalysis (Scheme 29). Depending on the added sulfoxide ligand, the linear (L) or branched (B) allylic acetate could be selectively obtained. With dimethylsulfoxide (DMSO), the linear product was the major isomer in excellent E diastereoselectivity,44 whereas with phenyl vinyl sulfoxide the branched product was formed regioselectively.45 A wide range of terminal olefins could be oxidized under these conditions, with yields ranging from 50 to 83 %. Carboxylic acids other than acetic acid could be employed, giving rise to a variety of allylic carboxylates. Mechanistic studies suggested that, during the catalytic cycle, the sulfoxide and benzoquinone act as serial ligands to promote the formation of the π-allyl intermediate (see Scheme 29) and the C[BOND]O coupling step, respectively.

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Scheme 29. Regioselective palladium(II)-catalyzed allylic C[BOND]H oxidation; TBDPS=tert-butyl diphenylsilyl.

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The DMSO-promoted formation of linear allylic acetates was exploited in the synthesis of various synthetic intermediates relevant to natural product synthesis, and it was shown that this method compares favorably with more traditional routes that employ olefination reactions.46 On the other hand, the formation of branched allylic carboxylates was exploited in the development of a new macrolactonization strategy, which proved to be applicable to a wide range of macrocycles, such as salicylic lactones and cyclodepsipeptides (Scheme 30).47 In this case, a bis(sulfoxide)palladium(II) complex was used as the catalyst, again in combination with BQ.

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Scheme 30. Macrolactonization by palladium(II)-catalyzed allylic C[BOND]H oxidation.

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Another elegant extension of this work consisted of performing a sequential allylic C[BOND]H oxidation/vinylic C[BOND]H arylation from terminal alkenes, which gives rise to functionalized styrenes with high regio- and E stereoselectivity (Scheme 31).48 The products obtained in this process are relevant to the synthesis of complex molecules, such as bryostatin 1 and a dipeptidyl peptidase inhibitor.

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Scheme 31. Sequential palladium(II)-catalyzed allylic C[BOND]H oxidation/vinylic C[BOND]H arylation.

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An asymmetric version of the allylic acetoxylation (Scheme 32) was reported more recently by White et al.49 By using a chiral [CrIIIF(salen)] Lewis acid as the co-catalyst, ees of up to 63 % could be achieved for the branched oxidation product, which was formed with a lower regioselectivity compared to the racemic version. The chiral Lewis acid was proposed to bind to BQ in the BQ-π-allylpalladium complex to account for the observed face selectivity.

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Scheme 32. Enantioselective palladium(II)-catalyzed allylic C[BOND]H oxidation.

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The extension of allylic C[BOND]H oxidation to allylic C[BOND]H amination was also reported by White et al., first in the intramolecular mode starting with homoallylic N-tosylcarbamates (Scheme 33).50 The corresponding N-tosyloxazolidinones were obtained in good yields and moderate to very good trans diastereoselectivity by using the same bis(sulfoxide)palladium(II) complex as described above and phenylbenzoquinone (PhBQ) instead of BQ. More recently, Liu and co-workers reported a related intramolecular allylic amination from N-tosylamides to regioselectively form five- to seven-membered lactams.51

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Scheme 33. Palladium(II)-catalyzed intramolecular allylic C[BOND]H amination.

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The intermolecular allylic amination was subsequently developed by the groups of White52 and Liu.53 Both used O-methyl-N-tosylcarbamate as the amination reagent along with palladium(II) catalysis, but under different conditions (Scheme 34). On the one hand, White et al. used the above-mentioned PdII–bis(sulfoxide) complex in combination with a [CrIIICl(salen)] Lewis acid catalyst, benzoquinone, and a two-fold excess of carbamate to obtain the linear allylic N-tosylcarbamate in good yield and high regio- and E diastereoselectivity. Surprisingly, the same palladium complex, which before gave branched allylic carboxylates, gave the linear allylic amination product. On the other hand, Liu et al. employed palladium(II) acetate as the catalyst, with catalytic maleic anhydride and sodium acetate under oxygen (6 atm) to give the linear amination product, but often as a mixture with the nonallylic isomer. It seems that the chromium–salen Lewis acid and maleic anhydride play a similar role in promoting the nucleophilic attack of the carbamate nitrogen on the intermediate π-allylpalladium complex.

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Scheme 34. Palladium(II)-catalyzed intermolecular allylic C[BOND]H amination; TBME=tert-butyl methyl ether, DMA=N,N-dimethylacetamide.

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A somewhat related diamination of terminal olefins at allylic and homoallylic positions was described by Y. Shi and co-workers,54 and an enantioselective variant was disclosed shortly thereafter (Scheme 35).55 High regioselectivities and trans diastereoselectivities were observed, and high enantioselectivities could be achieved by using a chiral phosphoramidite ligand. The reaction was proposed to proceed by oxidative addition of the diaziridinone to palladium(0), followed by complexation of the alkene and formation of the π-allyl complex by intramolecular proton abstraction (see Scheme 35). Subsequent β-hydride elimination would give the corresponding diene, which would then undergo diamination in a second catalytic cycle.

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Scheme 35. Enantioselective palladium(0)-catalyzed intermolecular C[BOND]H diamination.

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Shi et al. found that the regioselectivity of the reaction could be altered by using the sulfur analogue of the nitrogen donor, which gives rise to terminal diaminated compounds (Scheme 36).56 To account for this switch in selectivity, the authors suggested that the π-allylpalladium intermediate does not undergo β-hydride elimination to give the diene as in the previous case, but rather intramolecular amination at the terminal position (see Scheme 36) and then Pd-catalyzed intramolecular amination of the resulting internal double bond in a separate catalytic cycle.

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Scheme 36. Palladium(0)-catalyzed intermolecular C[BOND]H diamination at terminal positions; fur=2-furyl.

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The groups of White and Shi independently reported inter- and intramolecular allylic C[BOND]H alkylation57 by extension of the preceding oxidation and amination methods (Scheme 37). In the first case, allylarenes were alkylated in an intermolecular fashion with benzoylnitromethane, methyl nitroacetate, or (phenylsulfonyl)nitromethane by using the bis(sulfoxide)palladium(II) catalyst.58 In the second case, the reaction was performed intra- or intermolecularly by using β-dicarbonyl compounds and somewhat similar conditions.59

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Scheme 37. Palladium(II)-catalyzed inter- and intramolecular allylic C[BOND]H alkylation.

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Other unsaturation-directed C[BOND]H activation reactions: In 2004, Sames et al. reported the iridium-catalyzed intramolecular vinylation of a C[BOND]H bond adjacent to a nitrogen pyrrolidine (Scheme 38).60 By using [IrCl(coe)2]2 in combination with the N-heterocyclic carbene IPr as the catalyst and norbornene as the hydrogen acceptor, the 5-exo cyclization product was formed in good yield, together with a minor amount of the 6-endo cyclization isomer.

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Scheme 38. Iridium-catalyzed intramolecular C[BOND]H vinylation; coe=cyclooctene.

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Brookhardt and co-workers reported the cobalt- or rhodium-catalyzed intramolecular transfer dehydrogenation of cyclic amines by using an internal vinylsilane acceptor (Scheme 39).61 This reaction constitutes the intramolecular version of the intermolecular alkane dehydrogenation that was developed earlier by the same group, as well as by others (vide infra).

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Scheme 39. Cobalt- and rhodium-catalyzed intramolecular transfer dehydrogenation.

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Finally, the platinum(II)-catalyzed cyclization of o-substituted aryl akynes was recently described by He et al. (Scheme 40).62 Based on deuterium labeling experiments, the authors propose that the reaction proceeds by coordination of PtCl2 to the alkyne and subsequent formation of a 6-membered platinacycle (see Scheme 40). The beneficial role of the added copper(I) salt was not elucidated.

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Scheme 40. Platinum-catalyzed alkane/alkyne cyclization.

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Oxidative-Addition-Directed C[BOND]H Activation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

The oxidative addition of a carbon–halogen bond to a transition-metal complex gives rise to an organometallic intermediate that can behave similarly to the coordination complexes in the preceding section and, therefore, undergo intramolecular C[BOND]H activation in the same way, generally via a base-mediated proton abstraction (Scheme 41). A metallacycle containing two carbon–metal bonds is thus produced as the intermediate, and can subsequently give rise to carbo- or heterocycles by insertion or direct reductive elimination (paths a, b), to olefins by β-hydride elimination (path c), or functionalized hydrocarbons by transmetalation (path d).

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Scheme 41. Oxidative-addition-directed activation.

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Cyclisation reactions: A seminal example of a non-catalytic, palladium(0)-mediated reaction that features an intramolecular C[BOND]H activation followed by 1,2-insertion (Scheme 41, path a) is shown in Scheme 42.63 The starting aryl iodide effected oxidative addition to palladium(0), followed by intramolecular C[BOND]H activation at the activated α position of the ethyl ester. The resulting five-membered palladacycle, which was isolated and characterized by X-ray diffraction analysis, underwent alkyne insertion and reductive elimination to give functionalized 2H-1-benzopyran.

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Scheme 42. Stoichiometric C[BOND]H activation/alkyne insertion.

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Catellani et al. observed a related Pd-catalyzed process in which 2,6-dimethyliodobenzene reacted with norbornene to give a fused five-membered carbocycle as the major product (Scheme 43).64 The reaction was proposed to proceed by oxidative addition, norbornene insertion, intramolecular C[BOND]H activation (giving rise to a six-membered palladacycle) and reductive elimination.

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Scheme 43. Palladium(0)-catalyzed C[BOND]H activation/alkene insertion.

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Several seminal papers on the synthesis of polycyclic systems by intramolecular C[BOND]H activation of aryl iodides were published by Dyker in the early 1990s.65 In one instance (Scheme 44), 2-iodoanisole underwent a trimerization to give a fused heterocycle in high yield in the presence of Pd(OAc)2 (10 mol %), potassium carbonate, and a quaternary ammonium salt.65a The reaction presumably involves an initial oxidative addition followed by intramolecular C[BOND]H activation as discussed above, and the resulting five-membered palladacycle underwent intermolecular coupling with two other molecules of substrate. The dimerization of 2-iodo-tert-butylbenzene following a similar mechanism was also disclosed,65c as well as bimolecular reactions starting from an aryl iodide and a bromoalkene.

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Scheme 44. Trimerization of 2-iodoanisole by palladium(0)-catalyzed C[BOND]H activation.

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More recently, we reported the palladium(0)-catalyzed formation of fused four- and five-membered carbocycles by a purely intramolecular reaction involving oxidative addition, C[BOND]H activation and direct reductive elimination (Scheme 41, path b).66 Depending on the nature of the alkyl group undergoing C[BOND]H activation and the nature of the phosphine ligand, different products were regioselectively formed. The activation of a methyl group gave rise to benzocyclobutenes in moderate-to-high yield by using P(tBu)3 as the ligand (Scheme 45),66c and these fused carbocycles have a high synthetic value.67 Indeed, benzocyclobutenes obtained in this manner were used in Diels–Alder cycloadditions and electrocyclizations to give functionalized polycycles, including the tetrahydroprotoberberine alkaloid coralydine.68 The mechanism of the formation of benzocyclobutenes was studied in detail computationally,66c and it was shown that C(sp3)[BOND]H activation most likely occurs through a carbonate-mediated concerted metalation–deprotonation (CMD) pathway, which is related to the mechanism proposed for C(sp2)[BOND]H activation reactions.5, 69

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Scheme 45. Synthesis of benzocyclobutenes by palladium(0)-catalyzed C[BOND]H activation/intramolecular C[BOND]C coupling.

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On the other hand, the activation of branched alkyl groups gave rise to fused five-membered carbocycles in moderate yields but excellent diastereoselectivity (Scheme 46).66b In this case the intramolecular C[BOND]H activation gave a six-membered palladacyclic intermediate, whereas in the previous case a five-membered palladacycle was involved.

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Scheme 46. Synthesis of indanes by palladium(0)-catalyzed C[BOND]H activation/intramolecular C[BOND]C coupling.

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Two related reports described the formation of analogous fused five-membered heterocycles by intramolecular C[BOND]H activation of alkyl groups. First, Fagnou et al. reported the synthesis of 2,2-dialkyldihydrobenzofurans (Scheme 47).70 Computational studies concurred with the involvement of the base-induced CMD pathway for the C[BOND]H activation step. Shortly thereafter, Ohno et al. described the synthesis of indolines from functionalized 2-bromoanilines by a very similar process and under almost identical conditions (Scheme 48).71

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Scheme 47. Synthesis of dihydrobenzofurans by palladium(0)-catalyzed C[BOND]H activation/intramolecular C[BOND]C coupling.

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Scheme 48. Synthesis of indolines by palladium(0)-catalyzed C[BOND]H activation/intramolecular C[BOND]C coupling.

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Neuville, Zhu et al. reported the synthesis of 3-benzoxazolylisoindolinones by a sequence that included a similar type of intramolecular C[BOND]H activation as the last step (Scheme 49).72 The C[BOND]H activation occurred in good yield and regioselectivity, despite the presence of other potentially reactive C[BOND]H bonds.

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Scheme 49. Synthesis of 3-benzoxazolylisoindolinones by palladium(0)-catalyzed C[BOND]H activation/intramolecular C[BOND]C coupling.

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A similar strategy was reported by Knochel et al. for the formation of fused heterocycles by intramolecular C[BOND]H activation of a pyrrole methyl substituent (Scheme 50).73 The reaction, which takes place at a more activated C[BOND]H bond (as compared with previous cases), probably involves a similar mechanism via a six-membered palladacyclic intermediate.

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Scheme 50. Synthesis of fused heterocycles by palladium(0)-catalyzed C[BOND]H activation/intramolecular C[BOND]C coupling.

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Hu and co-workers accessed similar types of fused five-membered carbocycles by a slightly different approach that involved the coupling of 1,2-dihalobenzenes with 2,6-dimethylphenylmagnesium reagents (Scheme 51).74 The initial oxidative addition of the dihalobenzene to palladium is supposed to generate a benzyne–PdII complex, which would give rise to a biarylpalladium species after transmetalation and carbopalladation (see Scheme 51). Intramolecular activation of a benzylic C[BOND]H bond would then generate a six-membered palladacycle that would give the five-membered carbocyclic product by reductive elimination. A variation of this method, in which the 1,2-dihalobenzene is replaced by an internal alkyne, was also reported by the same group.75

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Scheme 51. Synthesis of fused carbocycles by palladium(0)-catalyzed C[BOND]H activation/intramolecular C[BOND]C coupling.

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Finally, original fused carbocycles containing a cyclopropane ring were obtained by Liron and Knochel by a domino sequence comprised of alkene carbopalladation, intramolecular C[BOND]H activation of a methyl group, and reductive elimination (Scheme 52, top).76 The C[BOND]H activation step is quite remarkable because it is presumed to give rise to an unusual strained four-membered palladacycle. Analogous fused benzofurocyclopropanes were synthesized from alkene-substituted 2-bromophenols by Kim et al. by using a similar mechanism that involved the formation of a four-membered palladacycle by intramolecular C[BOND]H activation.77 Spirocyclopropranes were also obtained by starting from 1,1-disubstituted alkenes under modified reaction conditions (Scheme 52, bottom).76

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Scheme 52. Synthesis of cyclopropane-containing carbo- and heterocycles by palladium(0)-catalyzed carbopalladation/C[BOND]H activation/intramolecular C[BOND]C coupling.

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Dehydrogenation and intermolecular C[BOND]C coupling: The metallacycle formed by intramolecular C[BOND]H activation can undertake a different route besides insertion and direct reductive elimination (Scheme 41, path c). Indeed, protonation of the arene, presumably by the metal-bound protonated base formed in the C[BOND]H activation step,66c followed by subsequent β-hydride elimination can give rise to an olefin. This pathway was first reported by our group in bromobenzenes with a linear benzylic alkyl substituent, such as an ethyl group (Scheme 53, top).66a,b Several analogues of tris(2-methylphenyl)phosphine were synthesized and evaluated as potential palladium ligands for this reaction. The less basic tris(5-fluoro-2-methylphenyl)phosphine (F-TOTP, Scheme 46) gave a much higher TOF, which allowed the reaction to proceed in 90 min at 100 °C. The reaction was extended to other substrates with linear alkyl or cycloalkyl groups, and was applied to the synthesis of the antihypertensive drug verapamil (Scheme 53, bottom). More recently, a similar dehydrogenation reaction starting from o-alkylated or o-alkoxylated iodobenzenes was reported by Catellani et al.78

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Scheme 53. Palladium(0)-catalyzed C[BOND]H activation/β-H elimination.

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Cascade reactions involving a dehydrogenative C[BOND]H activation step were also reported by our group (Scheme 54).79 In particular, a dehydrogenation/intramolecular Mizoroki–Heck reaction cascade starting from a 2,6-dihalobenzene gave rise to an original exo-methylenebenzocyclobutene, which was further functionalized in a one-pot fashion by intermolecular Mizoroki–Heck coupling with an aryl bromide to give a polysubstituted benzocyclobutene as a single olefin isomer. For instance, a conformationally restricted analogue of the antimicrotubule natural product combretastatin A-4 was obtained in moderate overall yield by this sequence.

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Scheme 54. Palladium(0)-catalyzed sequential C[BOND]H activation/intra- and intermolecular Mizoroki–Heck coupling.

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Another interesting outcome of the metallacycle formed by intramolecular C[BOND]H activation (Scheme 41, path d) was described by Buchwald and co-workers (Scheme 55).80 In the course of a study on the Suzuki–Miyaura coupling of bulky aryl bromides, they observed the formation of an unexpected product in high yield, which arose from C[BOND]C coupling at the ortho tert-butyl group. Mechanistically, the reaction presumably proceeds similarly to that described above (Scheme 53) by oxidative addition, intramolecular C[BOND]H activation to form a five-membered palladacycle, then protonation of the arene, transmetalation of the boronic acid, and reductive elimination.

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Scheme 55. Palladium(0)-catalyzed C[BOND]H activation/intermolecular C[BOND]C coupling.

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Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

Recently, Fagnou et al. reported a powerful method for the synthesis of fused pyrroles by palladium(II)-catalyzed tandem C[BOND]H activation reactions (Scheme 56).81 This method is somewhat related to a previous work by these authors on tandem C(sp2)[BOND]H/C(sp2)[BOND]H activation.82 The proposed mechanism involves a reversible palladation, that is, a C(sp2)[BOND]H activation step, followed by intramolecular C(sp3)[BOND]H activation to give a six-membered palladacycle that gives rise to the cyclization product by reductive elimination. Remarkably, the catalytic palladium(II) species was regenerated by using air as the sole oxidant. The reaction only proceeded efficiently with properly substituted pyrroles, which seems to constitute the most important limitation. The intramolecular C[BOND]H activation step is quite similar to that involved in heteroatom- and oxidative addition-directed reactions. However, if one considers that no directing group nor halogen atom is required and that air is the ideal stoichiometric oxidant, the present reaction constitutes a much more atom-economical process overall.

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Scheme 56. Palladium(II)-catalyzed tandem C(sp2)[BOND]H/C(sp3)[BOND]H activation.

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Intermolecular C[BOND]H Activation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

C[BOND]H borylation: The direct catalytic activation and functionalization of alkanes to introduce valuable synthetic groups has long been a challenging area of investigation in both organometallic and synthetic organic chemistry. Among the library of useful reagents, organoboron derivatives stand out as enablers for many chemical transformations, such as the Suzuki–Miyaura cross-coupling.83 A seminal work by Hartwig et al. described the catalytic C[BOND]H activation/borylation of pentane by using [Re(CO)3(Cp*)] under light irradiation to afford the monoborylated product in 95 % yield (based on the diboron reagent) in 56 h at room temperature (Scheme 57).84 This photochemical process is thought to involve two photoexpulsions of CO, which would in turn allow the oxidative addition of both reagents.

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Scheme 57. Rhenium-catalyzed photochemical C[BOND]H borylation.

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A further report by Hartwig et al. disclosed the discovery of more versatile rhodium(I) [Rh(η4-C6Me6)(Cp*)] and ruthenium(II) [(Cp*RuCl2)2] catalysts allowing a highly selective borylation of the least hindered terminal C[BOND]H bonds of alkyl groups (Scheme 58).85, 86 These catalysts, which allow the borylation to proceed under thermal conditions, have been proven to tolerate a variety of functional groups, such as tertiary amines, acetals, ethers, and fluoro derivatives. The reaction proceeded more efficiently in the neat alkane reagent. The boronate products were subsequently engaged in other transformations, such as Suzuki–Miyaura coupling (see Scheme 58).87

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Scheme 58. Rhodium-catalyzed thermal C[BOND]H borylation; Fc=ferrocene.

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Alkyl dehydrogenation: Because this reaction has already been reviewed,2, 3 it will be discussed only briefly in this chapter. In the early 1970s, breakthroughs in the field of transition-metal-catalyzed hydrogenation of alkenes triggered chemists’ imagination into understanding the reverse process. Generally, even though transition-metal-based catalysts can lower the large kinetic barrier associated with C[BOND]H bond cleavage, the back reaction of H2 with the generated unsaturated metal complex is thermodynamically favorable, making the overall process endothermic. Known systems that bypass this barrier use either the high heat of hydrogenation of a sacrificial H2 acceptor (Scheme 59) or photolysis as the driving force. Both systems are proposed to proceed by a C[BOND]H activation/β-hydride elimination mechanism.

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Scheme 59. Principles of transfer dehydrogenation.

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Following pioneering work by Crabtree et al.,88 Felkin’s group observed that rhenium complexes could catalyze the dehydrogenation of cyclooctane to yield cyclooctene in the presence of tert-butylethylene (TBE) to sustain the reactivity.89 Mainly rhenium,90 iridium,91 and rhodium92 catalysts have been developed towards thermal catalytic alkane transfer dehydrogenation (Table 1). The latest and most significant progress came through the use of pincer-type ligands, which stabilize the metal center and allow it to withstand the high reaction temperatures without significant decomposition.93 These may even allow acceptor-free reactions94 with turnovers as high as 3300 if using a phosphino-ferrocene-derived ligand.95 Brookhart et al. have applied such a catalyst in a nice example of tandem alkane dehydrogenation/olefin metathesis, in which the alkenes generated by olefin metathesis serve as sacrificial hydrogen acceptors to regenerate the dehydrogenation catalyst.96

Table 1. Iridium- and rhodium-catalyzed alkane dehydrogenation.inline image
CatalystRTONConditionsRef.
[ReH7{P(p-FC6H4)3}]tBu3.280 °C, 10 min90c
[IrH5{P(iPr)3}2]tBu70150 °C, 5 d91
[Rh(AsMe3)2Cl(CO)]H2460100 °C, 500 psi H2, 4 h92
[Ir(2,6-{CH2P(tBu)2}2C6H3)H2]tBu720200 °C, 1 h93a
[IrClH(2,6-{OP(tBu)2}2C6H3)]tBu2210200 °C, 2 weeks93b

Groundwork by Crabtree et al. showed that if the driving force for alkane dehydrogenation is supplied by a photon instead of a sacrificial alkene, the reaction can proceed under mild conditions (λ=254 nm, 25 °C) to give seven turnovers after 7 d.91e In this methodology, photons were thought to generate the active [Ir(CF3CO2)(PCy3)2] catalyst by expulsion of H2 from [Ir(CF3CO2)(H2)(PCy3)2]. Saito et al. were the first to describe photocatalytic dehydrogenation by using [RhCl(CO)(PMe3)] at 92 °C with a TOF of 795 h−1, which proves to be relatively high with respect to the methodologies that use sacrificial alkenes.97

Although the dehydrogenation of linear or cyclic unfunctionalized alkanes is of fundamental interest in chemical research, the application of such chemistry in organic synthesis remains at present very limited. In that prospect, Goldman et al. reported an interesting transfer-dehydrogenation of tertiary alkylamines by using a pincer-type IrIII complex and TBE as the sacrificial alkene to produce enamines in good-to-moderate yields. More highly substituted amines showed higher activities (Scheme 60).98

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Scheme 60. Iridium-catalyzed dehydrogenation of tertiary amines.

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Intermolecular C[BOND]C coupling: Recently, Murahashi’s group reported an intermolecular coupling between trifluoromethylated compounds with alkenes catalyzed by iridium or ruthenium complexes (Scheme 61).99 In the presence of either [Ru(Cp*)H(PPh3)2] or [IrH5{P(iPr)3}2] at room temperature, the resulting coupling products were obtained in good-to-excellent yields. Interestingly, the nature of the solvent played a significant role in this system, with apolar solvents such as toluene being optimal. The reaction is thought to proceed via the cleavage of the rather activated C[BOND]H bond α to the trifluoromethyl group by a low valent iridium or ruthenium species, with subsequent alkene insertion and reductive elimination to give the product. Control reactions run in the presence of a base gave only low conversions.

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Scheme 61. Iridium-catalyzed coupling of trifluoromethylated compounds with alkenes.

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Summary and Outlook

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

Extraordinary progress has been made in the past decade towards the functionalization of unreactive C[BOND]H bonds by transition-metal-catalyzed C[BOND]H activation.100 A variety of hydrocarbon hydrogen atoms can be cleaved and replaced by synthetically useful carbon- or heteroatom-based functional groups in a manner that is complementary to other C[BOND]H functionalization methods, such as C[BOND]H insertions. However, this area is still its in infancy and challenges still remain to improve its attractiveness for the synthesis of complex organic molecules. In particular, efforts to lower the reaction temperatures and decrease the catalyst loadings are expected. In addition, performing site-selective functionalizations of a given molecule at several types of C[BOND]H bonds would be of particular interest. Finally, the development of asymmetric C[BOND]H activation reactions for the control of newly created stereogenic centers represents a challenge of prime importance that has received very little attention so far.101

Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

Rodolphe Jazzar studied chemistry at the University of Poitiers (France). He completed his PhD in 2003 in the group of Mike Whittlesey in Bath (UK) on the synthesis and study of ruthenium carbene complexes. His PhD was followed by post-doctoral stays with Prof. E. P. Kündig (Geneva, Switzerland) and with Prof. G. Bertrand (Riverside, CA). He then joined the group of Prof. O. Baudoin at the University of Lyon 1 in 2006 and was appointed as a CNRS researcher within the same group in 2008. His main research focuses on organopalladium catalysis towards the synthesis of allenes and C[BOND]H activation.

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Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

Julien Hitce graduated from the Ecole Nationale Supérieure de Chimie de Paris (ENSCP) in 2004. He worked under the supervision of Dr. A. Marinetti in ENSCP during his Masters degree internship. He completed his PhD in 2007 under the guidance of Prof. O. Baudoin at the Institut de Chimie des Substances Naturelles in Gif-sur-Yvette, working on Pd-catalyzed C(sp3)[BOND]H activation. He then moved to Stanford University in 2008 for a post-doctoral stay under the supervision of Prof. B. M. Trost. Since 2009, he has worked as a research scientist at L′Oréal, where he is involved in the design and synthesis of novel cosmetic active ingredients in the context of green chemistry.

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Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

Alice Renaudat graduated from the Ecole Supérieure de Chimie Physique Electronique de Lyon (CPE) in 2007. In 2005–06, she did two six-months internships in Syngenta, first at the Crop Protection Centre in Basel (Switzerland) and then at Jeallot’s Hill International Research Centre (UK). She did her Master′s degree internship under the guidance of Dr. P. Belmont at the University of Lyon 1 in 2007, and she is currently pursuing her PhD on Pd-catalyzed C(sp3)[BOND]H activation at the same University under the supervision of Prof. O. Baudoin.

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Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

Julien Sofack-Kreutzer graduated from the University of Lyon 1 in 2008. In 2007, he spent six months doing an internship at Institut Français du Pétrole (IFP). He did his Master′s degree internship under the guidance of Prof. O. Baudoin at the University of Lyon 1 and is currently pursuing his PhD in the same group, working on Pd-catalyzed C(sp3)[BOND]H activation.

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Biographical Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Heteroatom-Directed C[BOND]H Activation
  5. Unsaturation-Directed C[BOND]H Activation
  6. Oxidative-Addition-Directed C[BOND]H Activation
  7. Tandem C(sp2)[BOND]H/C(sp3)[BOND]H Activation
  8. Intermolecular C[BOND]H Activation
  9. Summary and Outlook
  10. Acknowledgements
  11. Biographical Information
  12. Biographical Information
  13. Biographical Information
  14. Biographical Information
  15. Biographical Information

Olivier Baudoin studied chemistry at the Ecole Nationale Supérieure de Chimie de Paris (ENSCP). In 1998, he completed his PhD in the group of Jean-Marie Lehn in Paris on the synthesis and study of cyclo-bisintercaland molecules. He then worked as a post-doctoral fellow with K. C. Nicolaou in the Scripps Research Institute (La Jolla, CA). He joined the Institut de Chimie des Substances Naturelles (Gif-sur-Yvette) in 1999 as a CNRS researcher, and obtained his Habilitation diploma in 2004. In 2006, he was appointed Associate Professor at the University of Lyon 1. His main research focuses on organopalladium catalysis and in particular C(sp3)[BOND]H activation. He was the recipient of the CNRS Bronze Medal in 2005 and was nominated as a junior member of Institut Universitaire de France in 2009.

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